The reversible acetylation of histones and other proteins is a major mechanism for cellular regulation. Acetylation on protein lysine residues is catalyzed by histone acetyltransferases (HATs) and acetyl-Lys cleavage is performed by histone deacetylases (HDACs). These enzymes and the associated acetylation events have been implicated in a wide variety of physiological and disease processes, including tumorogenesis.
While studies on histone deacetylases have led to the discovery of highly potent compounds with clinical impact in cancer, the identification of histone acetyltransferase inhibitors has proved to be more challenging. For example, the most potent and selective compound, Lys-CoA, has been converted to a cell permeable form with Tat peptide attachment (Lys-CoA-Tat) and has been used in a variety of studies. However, the complexity of Lys-CoA-Tat limits its use in pharmacologic applications. High throughput screening experiments have led to the identification of several small molecule synthetic agents and natural product derivatives of moderate potency as p300/CBP HAT inhibitors, but their selectivity and mechanism of inhibition remains to be fully characterized.
Thus, there is a need in the art for the identification of novel HAT inhibitors. Characterization of novel HAT inhibitors are necessary to better understand the role of HATs in tumorogenesis, and as described herein, for use in treating cancers.